{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T05:34:47Z","timestamp":1790141687766,"version":"4.0.1"},"reference-count":50,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2018,1,1]],"date-time":"2018-01-01T00:00:00Z","timestamp":1514764800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Office of the Assistant Secretary of Defense for Health Affairs","award":["W81XWH-14-2-0017"],"award-info":[{"award-number":["W81XWH-14-2-0017"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2018,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Given the limitations of current antileishmanial drugs and the utility of oral combination therapy for other infections, developing an oral combination against visceral leishmaniasis should be a high priority.<jats:italic>In vitro<\/jats:italic>combination studies with DB766 and antifungal azoles against intracellular<jats:named-content content-type=\"genus-species\">Leishmania donovani<\/jats:named-content>showed that posaconazole and ketoconazole, but not fluconazole, enhanced DB766 potency. Pharmacokinetic analysis of DB766-azole combinations in uninfected Swiss Webster mice revealed that DB766 exposure was increased by higher posaconazole and ketoconazole doses, while DB766 decreased ketoconazole exposure. In<jats:named-content content-type=\"genus-species\">L. donovani<\/jats:named-content>-infected BALB\/c mice, DB766-posaconazole combinations given orally for 5 days were more effective than DB766 or posaconazole alone. For example, 81% \u00b1 1% (means \u00b1 standard errors) inhibition of liver parasite burden was observed for 37.5 mg\/kg of body weight DB766 plus 15 mg\/kg posaconazole, while 37.5 mg\/kg DB766 and 15 mg\/kg posaconazole administered as monotherapy gave 40% \u00b1 5% and 21% \u00b1 3% inhibition, respectively. Combination index (CI) analysis indicated that synergy or moderate synergy was observed in six of nine combined dose groups, while the other three were nearly additive. Liver concentrations of DB766 and posaconazole increased in almost all combination groups compared to monotherapy groups, although many increases were not statistically significant. For DB766-ketoconazole combinations evaluated in this model, two were antagonistic, one displayed synergy, and one was nearly additive. These data indicate that the efficacy of DB766-posaconazole and DB766-ketoconazole combinations<jats:italic>in vivo<\/jats:italic>is influenced in part by the pharmacokinetics of the combination, and that the former combination deserves further consideration in developing new treatment strategies against visceral leishmaniasis.<\/jats:p>","DOI":"10.1128\/aac.01129-17","type":"journal-article","created":{"date-parts":[[2017,10,24]],"date-time":"2017-10-24T00:40:25Z","timestamp":1508805625000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":15,"title":["Antileishmanial Efficacy and Pharmacokinetics of DB766-Azole Combinations"],"prefix":"10.1128","volume":"62","author":[{"given":"April C.","family":"Joice","sequence":"first","affiliation":[{"name":"Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1751-4975","authenticated-orcid":false,"given":"Sihyung","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdelbasset A.","family":"Farahat","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Georgia State University, Atlanta, Georgia, USA"},{"name":"Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi","family":"Meeds","sequence":"additional","affiliation":[{"name":"Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junan","family":"Li","sequence":"additional","affiliation":[{"name":"College of Pharmacy, The Ohio State University, Columbus, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W.","family":"Boykin","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Georgia State University, Atlanta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael Zhuo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl A.","family":"Werbovetz","sequence":"additional","affiliation":[{"name":"Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1517\/14656566.2015.973850"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00250-10"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2011.06.026"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2012.06.037"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2012.06.058"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.06404-11"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02405-14"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0025273"},{"key":"e_1_3_3_10_2","first-page":"392","article-title":"The efficacy and safety of ketoconazole in visceral leishmaniasis","volume":"71","author":"Rashid J","year":"1994","unstructured":"Rashid J, Wasunna K, Gachihi G, Nyakundi P, Mbugua J, Kirigi G. 1994. The efficacy and safety of ketoconazole in visceral leishmaniasis. East Afr Med J 71:392\u2013395.","journal-title":"East Afr Med J"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)64828-3"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01498-10"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm5000408"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2015.02.020"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0001671"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1089\/adt.2015.652"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1177\/108705719900400206"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2008.11.031"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1086\/600105"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1124\/pr.58.3.10"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1080\/10428190802353591"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.03947-14"},{"key":"e_1_3_3_23_2","first-page":"97","article-title":"Synergistic combination of microtubule targeting anticancer fludelone with cytoprotective panaxytriol derived from panax ginseng against MX-1 cells in vitro: experimental design and data analysis using the combination index method","volume":"6","author":"Zhang N","year":"2016","unstructured":"Zhang N, Fu J-N, Chou T-C. 2016. Synergistic combination of microtubule targeting anticancer fludelone with cytoprotective panaxytriol derived from panax ginseng against MX-1 cells in vitro: experimental design and data analysis using the combination index method. Am J Cancer Res 6:97\u2013104.","journal-title":"Am J Cancer Res"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.44.9.2373-2381.2000"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.44.3.739-746.2000"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkm493"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01397-07"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.04545-14"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0002977"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01150-15"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.2005.72.600"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/0166-6851(88)90166-1"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00436-013-3274-x"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.12.2910"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.1.172"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00041-08"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.05412-11"},{"key":"e_1_3_3_38_2","doi-asserted-by":"crossref","first-page":"344","DOI":"10.4049\/jimmunol.129.1.344","article-title":"Cell-mediated immune response in experimental visceral leishmaniasis. I. Correlation between resistance to Leishmania donovani and lymphokine-generating capacity","volume":"129","author":"Murray H","year":"1982","unstructured":"Murray H, Masur H, Keithly J. 1982. Cell-mediated immune response in experimental visceral leishmaniasis. I. Correlation between resistance to Leishmania donovani and lymphokine-generating capacity. J Immunol 129:344\u2013350.","journal-title":"J Immunol"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2004.01.005"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1517\/14656566.7.6.639"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1086\/591972"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)62050-8"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0001674"},{"key":"e_1_3_3_44_2","doi-asserted-by":"crossref","first-page":"214","DOI":"10.7555\/JBR.29.20140072","article-title":"In vitro activity and in vivo efficacy of a combination therapy of diminazene and chloroquine against murine visceral leishmaniasis","volume":"29","author":"Mwololo S","year":"2015","unstructured":"Mwololo S, Mutiso J, Macharia J, Bourdichon A, Gicheru M. 2015. In vitro activity and in vivo efficacy of a combination therapy of diminazene and chloroquine against murine visceral leishmaniasis. J Biomed Res 29:214\u2013223.","journal-title":"J Biomed Res"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00137-11"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.40.3.586"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.50.1.73-79.2006"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkg301"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1080\/00034983.1990.11812509"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.106.010587"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02605-14"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.01129-17","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.01129-17","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,27]],"date-time":"2023-08-27T13:04:16Z","timestamp":1693141456000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.01129-17"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,1]]},"references-count":50,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2018,1]]}},"alternative-id":["10.1128\/AAC.01129-17"],"URL":"https:\/\/doi.org\/10.1128\/aac.01129-17","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,1]]},"assertion":[{"value":"2017-05-31","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-10-18","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-12-21","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01129-17"}}